CN104974221A - Dipeptide and tripeptide proteasome inhibitors as well as preparation method and pharmaceutical application thereof - Google Patents
Dipeptide and tripeptide proteasome inhibitors as well as preparation method and pharmaceutical application thereof Download PDFInfo
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- CN104974221A CN104974221A CN201410133493.6A CN201410133493A CN104974221A CN 104974221 A CN104974221 A CN 104974221A CN 201410133493 A CN201410133493 A CN 201410133493A CN 104974221 A CN104974221 A CN 104974221A
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- 0 CC(C)C(C(NCc1c(*)cc(*)cc1)=O)*(C(C(*C(C(C1=CNC2C=CC=CC12)=O)=O)C1)=O)=C1N Chemical compound CC(C)C(C(NCc1c(*)cc(*)cc1)=O)*(C(C(*C(C(C1=CNC2C=CC=CC12)=O)=O)C1)=O)=C1N 0.000 description 5
- LUPQUUFBZDZNOS-XKSOPWPPSA-N CC(C)[C@@H](C(NCC1C=CC(C)=CC1)=O)NC(C(CC(N)=O)NC(Cc1cccc(Oc2ccccc2)c1)=O)=O Chemical compound CC(C)[C@@H](C(NCC1C=CC(C)=CC1)=O)NC(C(CC(N)=O)NC(Cc1cccc(Oc2ccccc2)c1)=O)=O LUPQUUFBZDZNOS-XKSOPWPPSA-N 0.000 description 1
- PSELAPQDIJJMQQ-KGICLZFCSA-N CC(C)[C@@H](C(NCc(c(O)c1)ccc1OC)=O)NC([C@@](C1)(C1C(N)=O)NC(Cc1c(C)[s]c(-c2ccccc2)n1)=O)=O Chemical compound CC(C)[C@@H](C(NCc(c(O)c1)ccc1OC)=O)NC([C@@](C1)(C1C(N)=O)NC(Cc1c(C)[s]c(-c2ccccc2)n1)=O)=O PSELAPQDIJJMQQ-KGICLZFCSA-N 0.000 description 1
- DDXXUEUECQIXQC-LVXARBLLSA-N CC(C)[C@@H](C(NCc(c(O)c1)ccc1OC)=O)NC([C@H](CC(N)=O)NC(Cc1c[o]c2c1ccc(OC)c2)=O)=O Chemical compound CC(C)[C@@H](C(NCc(c(O)c1)ccc1OC)=O)NC([C@H](CC(N)=O)NC(Cc1c[o]c2c1ccc(OC)c2)=O)=O DDXXUEUECQIXQC-LVXARBLLSA-N 0.000 description 1
- QFNJYECBFPOMEY-VWLOTQADSA-N CC(C)[C@@H](C(NCc(ccc(OC)c1)c1O)=O)NC(C(NC(Cc1c[nH]c2c1cccc2)=O)=C(C)C)=O Chemical compound CC(C)[C@@H](C(NCc(ccc(OC)c1)c1O)=O)NC(C(NC(Cc1c[nH]c2c1cccc2)=O)=C(C)C)=O QFNJYECBFPOMEY-VWLOTQADSA-N 0.000 description 1
- PDAHOWAGRXCYJB-WNJJXGMVSA-N CC(C)[C@@H](C(NCc1ccccc1C)=O)NC([C@H](CC(N)=O)NC(Cc1cccc(Oc2ccccc2)c1)=O)=O Chemical compound CC(C)[C@@H](C(NCc1ccccc1C)=O)NC([C@H](CC(N)=O)NC(Cc1cccc(Oc2ccccc2)c1)=O)=O PDAHOWAGRXCYJB-WNJJXGMVSA-N 0.000 description 1
- IGHWCJWROTUTBX-OYJHOXBRSA-N CC(C)[C@@H](C(N[C@@H]([C@@H](C)O)C(OC)=O)=O)NC([C@H](CC(N)=O)NC(Cc1cccc(Oc2ccccc2)c1)=O)=O Chemical compound CC(C)[C@@H](C(N[C@@H]([C@@H](C)O)C(OC)=O)=O)NC([C@H](CC(N)=O)NC(Cc1cccc(Oc2ccccc2)c1)=O)=O IGHWCJWROTUTBX-OYJHOXBRSA-N 0.000 description 1
Abstract
The invention discloses new dipeptide and tripeptide compounds shown in formulas I and II as well as stereoisomers and physiologically acceptable salt thereof, a preparation method of the compounds, a pharmaceutical preparation containing the compounds and a clinical application of the compounds in treatment of proteasome-related diseases.
Description
Technical field
The present invention relates to dipeptides and the tripeptides class new compound of general formula I and II, and their steric isomer and physiologically acceptable salt.The purposes of these compounds in the therapeutic process of the disease relevant to proteasome, also relates to the method that it is used for the treatment of, and the pharmaceutical composition containing described compound.
Background technology
Ubiquitin-proteasome path is the main path of protein degradation in eukaryotic cell, cell division, break up, grow, play an important role in the process such as intracellular signaling and apoptosis.Proteasome inhibitor Bortezomib and Carfilzomib is ratified listing by FDA and is used for the treatment of multiple myeloma, demonstrates the target spot that proteasome can be used as antitumor drug.Because two medicines gone on the market are covalent type proteasome inhibitor, covalent attachment pattern may cause serious toxic side effect, Shortcomings on drug safety, but not covalently bound proteasome inhibitor is then expected to overcome the problems referred to above, therefore, find novel non-covalent type proteasome inhibitor and have important meaning.
At present, less to the proteasome inhibitor research of non-covalent type.In the present invention, our the non-covalent type proteasome inhibitor TMC-95A based on natural origin and complex crystal structure of proteasome, the straight chain dipeptides that a series of novel structure of design and synthesis and being easy to synthesizes and three peptides, and confirm that most new compound has good proteasome restraining effect through biological assessment.
Summary of the invention
The object of the present invention is to provide new dipeptides and three peptides of a kind of formula I and II.
Another object of the present invention is to provide the new dipeptides of a kind of preparation formula I and II and the method for three peptides.
Another object of the present invention is the new dipeptides and the purposes of three peptides in proteasome enzyme inhibition that provide formula I and II, and treats the purposes in the disease relevant with proteasome.
In order to complete object of the present invention, the present invention adopts following technical scheme:
The present invention relates to have the new dipeptides of general formula I and II and three peptides and steric isomer thereof and physiologically acceptable salt.
Wherein, L is selected from covalent linkage ,-CO-, or-(CH
2) n-, n=1,2;
R
1be selected from substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl;
R
2be selected from substituted or unsubstituted C1-C6 straight or branched alkyl;
R
3be selected from (CH
2) mCONH
2, m=1,2,3, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
4be selected from substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substituted or unsubstituted indyl, substituted or unsubstituted quinolyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted cumarone ketone group.
Substituting group is selected from hydroxyl, amino, halogen, phenyl, C1-C3 alkyl, C1-C3 haloalkyl, aryloxy, C1-C3 alkoxyl group, sweet-smelling formacyl, benzyloxy.
Preferred formula (I) compound, including but not limited to the compound shown in (IA) and steric isomer thereof and physiologically acceptable salt.
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
4be selected from substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substituted or unsubstituted indyl, substituted or unsubstituted quinolyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzofuranone.
Substituting group is selected from hydroxyl, amino, halogen, phenyl, C1-C3 alkyl, C1-C3 haloalkyl, aryloxy, C1-C3 alkoxyl group, sweet-smelling formacyl, benzyloxy.
Preferred formula (IA) compound, including but not limited to the compound shown in (IAa) and steric isomer thereof and physiologically acceptable salt.
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
41, R
42separately be selected from hydrogen, methoxyl group, trifluoromethyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy group, substituted or unsubstituted benzoyl.
Substituting group is selected from hydroxyl, amino, halogen, phenyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (IA) compound, including but not limited to the compound shown in (IAb) and three-dimensional different
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
43be selected from hydrogen, halogen, hydroxyl, amino, nitro.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (IA) compound, including but not limited to the compound shown in (IAc) and steric isomer thereof and physiologically acceptable salt.
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
44be selected from hydrogen, halogen, hydroxyl, amino, nitro.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (IA) compound, including but not limited to the compound shown in (IAd) and steric isomer thereof and physiologically acceptable salt.
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
45, R
46separately be selected from substituted or unsubstituted C1-C6 straight or branched alkyl;
Substituting group is selected from hydroxyl, amino, halogen, phenyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (IA) compound, including but not limited to the compound shown in (IAe) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
47be selected from hydrogen, halogen, hydroxyl, amino, nitro.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (IA) compound, including but not limited to the compound shown in (IAf) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
48be selected from hydrogen, halogen, hydroxyl, amino, nitro.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (I) compound, including but not limited to the compound shown in (IB) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
49be selected from substituted or unsubstituted benzyloxy.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (I) compound, including but not limited to the compound shown in (IC) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
410be selected from hydrogen, halogen, hydroxyl, amino, nitro.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (I) compound, including but not limited to the compound shown in (ID) and steric isomer thereof and physiologically acceptable salt
R
13be selected from hydrogen, halogen, hydroxyl, amino, nitro;
R
411be selected from substituted or unsubstituted phenoxy group;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (I) compound, including but not limited to the compound shown in (IE) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
412be selected from substituted or unsubstituted phenoxy group.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (I) compound, including but not limited to the compound shown in (IF) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
31, R
32separately be selected from hydrogen, hydroxyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
413be selected from substituted or unsubstituted phenoxy group.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (I) compound, including but not limited to the compound shown in (IG) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
31, R
32separately be selected from hydrogen, hydroxyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
414be selected from hydrogen, halogen, hydroxyl, amino, nitro.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
The tripeptide compound that general formula (II) represents and steric isomer thereof and physiologically acceptable salt
Wherein, M is selected from-(CH
2)
n-, n=0,1,2;
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
6be selected from hydrogen, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
7be selected from substituted or unsubstituted C1-C6 straight or branched alkyl;
R
8be selected from (CH
2) mCONH
2, m=1,2,3, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
9be selected from substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy group, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substituted or unsubstituted indyl;
Substituting group is selected from hydroxyl, amino, halogen, phenyl, C1-C3 alkyl, C1-C3 haloalkyl, aryloxy, C1-C3 alkoxyl group, sweet-smelling formacyl, benzyloxy.
Preferred formula (II) compound, including but not limited to the compound shown in (IIA) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
91, R
92separately be selected from hydrogen, substituted or unsubstituted phenoxy group, substituted or unsubstituted phenyl;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (II) compound, including but not limited to the compound shown in (IIB) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
93be selected from substituted or unsubstituted phenoxy group, substituted or unsubstituted phenyl;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (II) compound, including but not limited to the compound shown in (IIC) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
94be selected from hydrogen, halogen, hydroxyl, amino, nitro.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (II) compound, including but not limited to the compound shown in (IID) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
95be selected from C3-C6 cycloalkyl.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (II) compound, including but not limited to the compound shown in (IIE) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
96be selected from hydrogen, halogen, hydroxyl, amino, nitro.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Preferred formula (II) compound, including but not limited to the compound shown in (IIF) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
97, R
98, R
99separately be selected from substituted or unsubstituted C1-C6 straight or branched alkoxyl group.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
Most preferred compound is selected from following group:
According to the present invention, the compounds of this invention can the form of steric isomer exist, and usually described " the compounds of this invention " comprises the steric isomer of this compound.
The formula V compound that formula III compound and formula IV compound generate through condensation reaction; formula V compound is through deprotection reaction production VI compound; formula VI compound and formula VII compound are through condensation reaction production VIII compound; formula VIII compound is through deprotection reaction production IX compound, and formula IX compound and formula X compound are through condensation reaction production I.
Wherein, L, R
1, R
2, R
3and R
4definition the same.
The formula XIII compound that formula XI compound and formula XII compound generate through condensation reaction; formula XIII compound is through deprotection reaction production XIV compound; formula XIV compound and formula XV compound are through condensation reaction production XVI compound; formula XVI compound is through deprotection reaction production XVII compound, and formula XVII compound and formula XVIII compound are through condensation reaction production II compound.
Wherein, M, R
5, R
6, R
7, R
8and R
9definition the same.
The present invention also relates to the pharmaceutical composition using the compounds of this invention as activeconstituents on the other hand.This pharmaceutical composition is prepared according to method well known in the art.By pharmaceutically acceptable to the compounds of this invention and one or more solid or liquid excipient and/or assistant agent being combined, make any formulation being suitable for human or animal and using.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition containing it can administrations in a unit, route of administration is enteron aisle or non-bowel, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
In order to the compounds of this invention is made tablet, various vehicle well known in the art can be widely used, comprise thinner, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, hydroxypropylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, pin chain polyethylene pyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet can also be made coating tablet further, such as sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
In order to administration unit is made capsule, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in hard capsule or soft capsule.Also effective constituent the compounds of this invention particle or micropill be can be made prior to thinner, tamanori, disintegrating agent, then hard capsule or soft capsule are placed in.Also the capsule preparing the compounds of this invention is can be used for for the preparation of each thinner of the compounds of this invention tablet, tamanori, wetting agent, disintegrating agent, glidant kind.
For the compounds of this invention is made injection, appropriate this area conventional solubilizing agent, solubility promoter, pH adjusting agent, osmotic pressure regulator can be added with water, ethanol, Virahol, propylene glycol or their mixture as solvent.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjusting agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepared lyophilized injectable powder, figure N.F,USP MANNITOL, glucose etc. also can be added as propping agent.
In addition, as needs, also tinting material, sanitas, spices, correctives or other additive can be added in pharmaceutical preparation.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to preventing or the character of disease therapy and severity, and the individual instances of patient or animal, route of administration and formulation etc. can have large-scale change.In general, suitable dose every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.1-100mg/Kg body weight, is more preferably 1-60mg/Kg body weight, most preferably is 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or be divided into several dosage unit administration, and this depends on the clinical experience of doctor and comprises the dosage regimen using other treatment means.
Compound of the present invention or composition can be taken separately, or merge with other treatment medicine or symptomatic drugs and use.When compound of the present invention and other medicine exist act synergistically time, its dosage should be adjusted according to practical situation.
Pharmaceutical research shows, general formula I of the present invention and II compound have the activity of proteasome enzyme inhibition, and for the disease relevant to proteasome activity, as inflammation, tumour, especially multiple myeloma etc. have effect.
Embodiment
Below in conjunction with embodiment, invention is further described, but these embodiments do not limit the scope of the invention.
The structure of compound is determined by nucleus magnetic resonance (NMR) or mass spectrum (MS) or high resolution mass spectrum (HRMS).NMR displacement (δ) provides with the unit of 1,000,000/(ppm).M.p is with DEG C fusing point provided, the non-correction up of temperature.Column chromatography generally uses 200-300 order silica gel to be carrier.NMR measures and uses INOVA-300, and mensuration reagent is CD
3oD, DMSO-d
6, be inside designated as TMS, chemical shift provides using ppm as unit.The mensuration Agilent LC/MSD TOF LC-MS instrument of MS.
Abbreviation
TLC: thin-layer chromatography;
DMSO-d
6: hexadeuterated dimethyl sulfoxide;
CD
3oD: deuterated methanol;
DMF:N, dinethylformamide;
DIEA:N, N-diisopropylethylamine
HATU:2-(7-azo benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester
Boc: tertbutyloxycarbonyl
Asn: l-asparagine
Bzl: benzyl
L-allo-Thr-OH: allothreonine
Tyr: tyrosine
Val: α-amino-isovaleric acid
Thr: Threonine
Gln: glutamine
Ser: Serine
TLC: thin-layer chromatography
Embodiment 1:WK-3-18
a）
2.1g white solid Boc-Asn-Val-OH (6.3mmol) is dissolved in 50mLDMF, add 1.2g2-hydroxyl-4-methoxybenzylamine hydrochloride (6.3mmol) respectively, 2.4gHATU (6.3mmol), 2.0gDIEA (15.75mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, remove solvent under reduced pressure, after acetic acid ethyl dissolution, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, after remaining organic over anhydrous dried over sodium sulfate, remove solvent under reduced pressure, wash by a small amount of ethyl acetate, filter to obtain white solid 2.5g, productive rate 85%.
b)
The white solid (0.57mmol) of gained in 266mg1a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 95mg4-methoxyphenylacetic acid (0.57mmol) respectively, 217mgHATU (0.57mmol), 184mgDIEA (0.57mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filters to obtain white solid 210mg, productive rate 71.7%.mp:217℃-218℃.
1HNMR(d-DMSO)δ9.60(s,1H),8.34(s,2H),7.66(s,1H),7.40(s,1H),7.15(d,2H,J=9.0Hz),6.91-6.98(m,1H),6.81(d,2H,J=9.0Hz),6.37-6.29(m,2H),4.37-4.33(m,2H),4.11(s,2H),3.70(s,3H),3.65(s,3H),3.37(s,2H),2.43-2.37(m,2H),2.00-1.94(m,1H),0.75-0.70(m,6H);MS-ESI m/z:515[M+H]
+。
Embodiment 2:WK-3-21
The white solid (0.43mmol) of gained in 200mg1a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 75mg3-indolylacetic acid (0.43mmol) respectively, 164mgHATU (0.43mmol), 139mgDIEA (0.57mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filters to obtain pale red solid 142mg, productive rate 63%.mp:214℃-215℃.
1H-NMR(CD
3OD)δ7.48(d,1H,J=9.0Hz),7.27(d,1H,J=9.0Hz),7.14(s,1H),7.06-6.92(m,3H),6.30-6.28(m,2H),4.72(t,1H,J=6.0Hz),4.18(s,2H),4.08-4.01(m,1H),3.70(s,5H),2.67-2.51(m,3H),0.72-0.66(m,6H);MS-ESI m/z:524(M+H)
+。
Embodiment 3:WK-3-24
The white solid (0.43mmol) of gained in 200mg1a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 91mg4-felbinac (0.43mmol) respectively, 164mgHATU (0.43mmol), 139mgDIEA (0.57mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, remove solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, wash by ethyl acetate, recrystallizing methanol after filtering, obtains white solid 105mg, productive rate 43.6%.mp:231℃-232℃.
1H-NMR(CD
3OD)δ7.51-7.46(m,4H),7.32-7.24(m,4H),6.97(d,2H,J=7.8Hz),6.35-6.28(m,2H),4.78-4.70(m,1H),4.18(s,2H),4.08-3.99(m,1H),3.63(s,3H),3.52(s,2H),2.69-2.53(m,3H),0.79-0.70(m,6H);MS-ESI m/z:561(M+H)
+。
Embodiment 4:WK-4-26
The white solid (0.43mmol) of gained in 200mg1a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 88mg4-trifluoromethyl phenylacetic acid (0.43mmol) respectively, 164mgHATU (0.43mmol), 139mgDIEA (0.57mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filters to obtain white solid 87mg, productive rate 36.6%.mp:227℃-228℃.
1H-NMR(DMSO-d
6)δ9.65(s,1H),8.65(d,1H,J=9.0Hz),8.34(s,1H),7.69-7.59(m,3H),7.48-7.45(m,3H),6.96-6.91(m,2H),6.39(s,1H),6.29(d,1H,J=6.0Hz),4.63-4.59(m,1H),4.14-4.09(m,3H),3.64(s,3H),3.57(s,2H),2.59-2.52(m,1H),2.43-2.37(m,1H),1.97-1.90(m,1H),0.71-0.65(m,6H);MS-ESI m/z:553[M+H]
+。
Embodiment 5:WK-4-29
The white solid (0.43mmol) of gained in 200mg1a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 100mg (5-methyl-2-phenyl-4-thiazolyl) acetic acid (0.43mmol) respectively, 164mgHATU (0.43mmol), 139mgDIEA (0.57mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, with methanol wash column, filters to obtain white solid 126mg, productive rate 50.4%.mp:215℃-216℃.
1H-NMR(DMSO-d
6)δ9.69(s,1H),8.44(d,1H,J=6.0Hz),8.36-8.32(m,1H),7.83-7.81(m,2H),7.69(d,1H,J=9.0Hz),7.46-7.44(m,4H),6.98-6.94(m,2H),6.36-6.30(m,2H),4.67-4.61(m,1H),4.17-4.10(m,3H),3.66(s,5H),2.62-2.56(m,1H),2.47-2.41(m,4H),2.00-1.94(m,1H),0.75-0.70(m,6H);MS-ESI m/z:582[M+H]
+。
Embodiment 6:WK-4-31
The white solid (0.43mmol) of gained in 200mg1a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 80mg α-naphthaleneacetic acid (0.43mmol) respectively, 164mgHATU (0.43mmol), 139mgDIEA (0.57mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, with methanol wash column, filters to obtain white solid 98mg, productive rate 42.6%.mp:235℃-236℃.
1H-NMR(DMSO-d
6)δ9.54(s,1H),8.52(d,1H,J=6.0Hz),8.34-8.32(m,1H),8.07-8.03(m,1H),7.90-7.87(m,1H),7.80-7.77(m,1H),7.70(d,1H,J=6.0Hz),7.50-7.47(m,2H),7.41-7.40(m,3H),6.97-6.92(m,2H),6.34-6.29(m,2H),4.67-4.61(m,1H),4.16-4.09(m,3H),3.93(s,2H),3.64(s,2H),2.61-2.54(m,1H),2.47-2.41(m,1H),1.97-1.91(m,1H),0.72-0.65(m,6H);MS-ESI m/z:535[M+H]。
Embodiment 7:WK-4-36
The white solid (0.43mmol) of gained in 200mg1a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 88mg5-methoxyl group-3-indolyl acetic acid (0.43mmol) respectively, 164mgHATU (0.43mmol), 139mgDIEA (1.075mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filters to obtain white solid 85mg, productive rate 35.7%.mp:206℃-208℃。
1H-NMR(DMSO-d6，300MHz)δ10.70(s,1H),8.36-8.26(m,2H),7.75(d,1H,J=9.0Hz),7.44(s,1H),7.20(d,1H,J=9.0Hz),7.14(s,1H),7.03(s,1H),6.98-6.90(m,2H),6.69(d,1H,J=6.0Hz),6.35(s,1H),6.30(d,1H,J=6.0Hz),4.66-4.62(m,1H),4.12-4.10(m,3H),3.75(s,3H),3.65(s,3H),3.51(s,2H),2.60-2.52(m,1H),2.45-2.37(m,1H),1.98-1.93(m,1H),0.73-0.68(m,6H);MS-ESI m/z:554[M+H]
+。
Embodiment 8:WK-5-11
The white solid (0.32mmol) of gained in 150mg1a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 73mg4-benzyloxy phenylformic acid (0.32mmol) respectively, 122mgHATU (0.32mmol), 103mgDIEA (0.8mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filters to obtain white solid 100mg, productive rate 54.2%.mp:217℃-218℃.
1H-NMR(DMSO-d
6,300MHz)δ:9.57(s,1H),8.54(d,1H,J=6.0Hz),8.36-8.34(m,1H),7.82(d,2H,J=9.0Hz),7.73(d,1H,J=9.0Hz),7.48-7.34(m,6H),7.09(d,2H,J=9.0Hz),7.00-6.97(m,1H),6.92(s,1H),6.36-6.32(m,2H),5.18(s,2H),4.83-4.77(m,1H),4.21-4.11(m,3H),3.67(s,3H),2.69-2.56(m,2H),2.02-1.95(m,1H),0.81-0.75(m,6H);MS-ESI m/z:577[M+H]
+。
Embodiment 9:WK-5-13
The white solid (0.43mmol) of gained in 200mg1a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 89mg2-(6-methoxyl group-1-cumarone-3-base) acetic acid (0.43mmol) respectively, 163mgHATU (0.43mmol), 139mgDIEA (1.075mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filters to obtain white solid 95mg, productive rate 40%.mp:204℃-206℃.
1H-NMR(DMSO-d6,300MHz)δ9.54(s,1H),8.46-8.40(m,1H),8.34-8.28(m,1H),7.73-7.69(m,1H),7.67(s,1H),7.47(d,1H,J=9.0Hz),7.39-7.36(m,1H),7.12-7.11(m,1H),6.98-6.92(m,2H),6.84-6.80(m,1H),6.34-6.26(m,2H),4.66-4.62(m,1H),4.16-4.09(m,3H),3.76(s,3H),3.64(s,3H),3.50(s,2H),2.59-2.52(m,1H),2.44-2.37(m,1H),1.99-1.93(m,1H),0.77-0.68(m,6H)l;MS-ESI m/z:555[M+H]
+。
Embodiment 10:WK-5-17
The white solid (0.43mmol) of gained in 200mg1a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 82mg phthalide-3-acetic acid (0.43mmol) respectively, 163mgHATU (0.43mmol), 139mgDIEA (1.075mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filters to obtain white solid 70mg, productive rate 30%.mp:262℃-263℃.
1H-NMR(DMSO-d
6,300MHZ)δ9.57(d,1H,J=3.0Hz),8.41-8.35(m,2H),7.85-7.71(m,4H),7.60(t,1H,J=9.0Hz),7.42(d,1H,J=9.0Hz),7.01-6.96(m,2H),6.36-6.31(m,2H),5.92-5.86(m,1H),4.75-4.71(m,1H),4.16-4.12(m,3H),3.66(s,2H),2.88-2.81(m,1H),2.75-2.67(m,1H),2.62-2.54(m,1H),2.45-2.37(m,1H),2.09-2.03(m,1H),0.85-0.83(m,6H);MS-ESI m/z:541[M+H]
+。
Embodiment 11:WK-5-19
The white solid (0.43mmol) of gained in 200mg1a is dissolved in 8mL methylene dichloride; add 2mL trifluoroacetic acid; stirring at room temperature is after 2 hours, and TLC detects, and reacts completely; remove solvent under reduced pressure; obtain white solid, be dissolved in 20mLDMF, add 103mg3-benzoylphenylacetic acids (0.43mmol) respectively; 163mgHATU (0.43mmol), 139mgDIEA (1.075mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, remove solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filter to obtain light yellow solid 163mg, productive rate 64.4%.mp:197℃-199℃.
1H-NMR(DMSO-d
6，300MHz)δ9.53(s,1H),8.46(d,1H,J=6.0Hz),8.34-8.30(m,1H),7.73-7.64(m,5H),7.57-7.52(m,4H),7.47(d,1H,J=6.0Hz),7.37(s,1H),6.96-6.90(m,2H),6.34-6.29(m,2H),4.65-4.58(m,1H),4.13-4.08(m,3H),3.64(s,3H),3.55(s,2H),2.60-2.52(m,1H),2.40-2.33(m,1H),1.97-1.90(m,1H),0.69-0.64(m,6H);MS-ESI m/z:589[M+H]
+。
Embodiment 12:WK-5-20
The white solid (0.43mmol) of gained in 200mg1a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 103mg3-indoleacetaldehyde acid (0.43mmol) respectively, 163mgHATU (0.43mmol), 139mgDIEA (1.075mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, remove solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filter to obtain pale red solid 116mg, productive rate 50.2%.mp:215℃-216℃.
1H-NMR(DMSO-d
6,300MH
Z)δ8.885(d,1H,J=9.0Hz),8.73(s,1H),8.37-8.33(m,1H),8.21(t,1H,J=6.0Hz),7.845(d,1H,J=9.0Hz),7.64-7.61(m,1H),7.43(s,1H),7.25-7.23(m,2H),6.98-6.95(m,2H),6.36-6.27(m,2H),4.75-4.68(m,1H),4.21-4.09(m,3H),3.63(s,3H),2.67-2.60(m,2H),2.02-1.94(m,1H),0.81-0.79(m,6H);MS-ESI.m/z:538[M+H]
+。
Embodiment 13:WK-5-2
a）
By 3.006g white solid Boc-Asn-Val-OBzl(7.13mmol) add in the mixing solutions of TFA/DCM (18mL/20mL), stirring at room temperature, spends the night, and TLC detects, and reacts completely, removes solvent under reduced pressure, obtain oily matter.Gained oily matter is dissolved in 40mLDMF, add 1.628g3-phenoxy group toluylic acid (7.13mmol), 2.715gHATU (7.13mmol), 9.228mgDIEA (7.13mmol) respectively, stirred overnight at room temperature, TLC detects, react completely, remove solvent under reduced pressure, after acetic acid ethyl dissolution, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, after anhydrous sodium sulfate drying, evaporated under reduced pressure, white solid 1.366g is obtained, productive rate 36% after silica gel column chromatography.
b）
In 1.366g13a, the white solid of gained is dissolved in 100mL methyl alcohol, adds 130mg10%Pd/C, and stirring under hydrogen spends the night, and TLC detects, and react completely, diatomite filtration, filtrate decompression evaporate to dryness, obtains white solid 1.040g, productive rate 91.7%.
c)
The white solid (0.5mmol) of gained in 220mg13b is dissolved in 20mLDMF, adds 0.06mL2-chlorobenzylamine (0.5mmol) respectively, 190mgHATU (0.5mmol), 162mgDIEA (1.25mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving, uses the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution with ethyl acetate portion, and distillation washing, filters to obtain white solid 207mg, productive rate 73.4%.mp:252.0-253.0℃.
1H-NMR(DMSO-d
6,300MHz)δ:8.52(t,1H,J=6.0Hz),8.41(d,1H,J=7.5Hz),7.81(d,1H,J=8.1Hz),7.41-7.36(m,4H),7.32-7.25(m,4H),7.13(t,1H,J=7.2Hz),7.05-6.95(m,5H),6.86-6.83(m,1H),4.68-4.62(m,1H),4.33-4.31(m,2H),4.19-4.14(m,1H),3.46(s,2H),2.62-2.55(m,1H),2.43-2.36(m,1H),2.08-2.01(m,1H),0.80-0.74(m,6H);MS-ESI m/z:565[M+H]
+。
Embodiment 14:WK-5-16
The white solid (0.47mmol) of gained in 208mg13b is dissolved in 20mLDMF, add respectively 0.06mL4-methylbenzylamine (0.5mmol) (0.47mmol), 179mgHATU (0.47mmol), 152mgDIEA (1.175mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving, uses the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution with ethyl acetate portion, and distillation washing, filters to obtain white solid 202mg, productive rate 79%.mp:249.0-250.0℃.
1H-NMR(DMSO-d
6,300MHz)δ:8.41-8.36(m,2H),7.67(d,1H,J=9.0Hz),7.38-7.34(m,3H),7.26(t,1H,J=7.5Hz),7.13-7.09(m,5H),7.02-6.93(m,5H),6.83-6.80(m,1H),4.64-4.58(m,1H),4.19-4.07(m,3H),3.44(s,2H),2.59-2.52(m,1H),2.40-2.32(m,1H),2.24(s,3H),2.00-1.96(m,1H),0.78-0.68(m,6H);MS-ESIm/z:545[M+H]
+。
Embodiment 15:WK-5-23
The white solid (0.3gmmol) of gained in 172mg13b is dissolved in 20mLDMF, add 0.04mL2-thiophene ethamine (0.39mmol) respectively, 148mgHATU (0.39mmol), 126mgDIEA (0.975mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving, uses the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution with ethyl acetate portion, and distillation washing, filters to obtain pale solid 153mg, productive rate 73.2%.mp:240.0-241.0℃.
1H-NMR(DMSO-d
6,300MHz)δ:8.58-8.51(m,1H),8.39-8.32(m,1H),7.67(d,1H,J=9.0Hz),7.39-7.34(m,4H),7.26(t,1H,J=7.5Hz),7.11(t,1H,J=7.5Hz),7.02-6.96(m,3H),6.92-6.89(m,4H),6.84-6.80(m,1H),4.64-4.58(m,1H),4.40-4.36(m,2sH),4.13-4.06(m,1H),3.44(s,2H),2.58-2.51(m,1H),2.40-2.32(m,1H),2.00-1.96(m,1H),0.78-0.69(m,6H);MS-ESIm/z:537[M+H]
+。
Embodiment 16:XK-6-23
The white solid (0.11mmol) of gained in 50mg13b is dissolved in 20mLDMF, add 17mg2-hydroxyl-4-methoxybenzylamine (0.11mmol) respectively, 42mgHATU (0.11mmol), 36mgDIEA (0.28mmol).Stirred overnight at room temperature, removes solvent under reduced pressure, column chromatography, obtains product 20mg, productive rate 31.5%.mp:201.0-203.0℃,
1H-NMR(CD
3OD)δ:7.29-7.17(m,3H),7.05-6.96(m,3H),6.92-6.89(m,3H),6.77(d,1H,J=8.7Hz),6.29-6.27(m,2H),4.68(t,1H,J=6.9Hz),4.18(s,2H),4.12-4.06(m,1H),3.64(s,3H),3.46(s,2H),3.08-3.02(m,2H),2.68(q,1H,J=7.2,15.6Hz),2.53(q,1H,J=6.6,15.6Hz),2.07-1.98(m,1H),0.75(t,6H,J=4.8Hz);MS-ESI m/z:577[M+H]
+。
Embodiment 17:XK-6-15
The white solid (0.5mmol) of gained in 220mg13b is dissolved in 20mLDMF, adds 84mg (0.5mmol) respectively, 190mgHATU (0.5mmol), 161mgDIEA (1.25mmol).Stirred overnight at room temperature, removes solvent under reduced pressure, column chromatography, obtains product 120mg, productive rate: 40.7%.mp:217.0-222.0℃；
1H-NMR(DMSO-d
6)δ:8.47(d,1H,J=7.5Hz),8.20(m,1H),7.66(d,1H,J=9.3Hz),7.43(s,1H),7.37(t,2H,J=7.5Hz),7.26(t,1H,J=7.8Hz),7.11(t,1H,J=7.2Hz),7.04-6.94(m,5H),6.88(s,1H),6.82(d,1H,J=7.2Hz),6.50(d,1H,J=2.1Hz),6.44(d,1H,J=8.1Hz),4.62-4.59(m,1H),4.17-4.12(m,3H),3.75(s,3H),3.72(s,3H),3.45(s,2H),2.59-2.49(m,1H),2.375(q,1H,J=6.6,15.6Hz),1.99-1.92(m,1H),0.74-0.69(m,6H);MS-ESI m/z:591[M+H]
+。
Embodiment 18:WK-4-34
a)
The white solid (5mmol) of gained in 1.086g Boc-Val-OH is dissolved in 20mLDMF, add 2-hydroxyl-4-methoxybenzylamine hydrochloride 948mg (5mmol) respectively, 1.9gHATU (5mmol), 1.61gDIEA (12.5mmol).Stirred overnight at room temperature, removes solvent under reduced pressure, after acetic acid ethyl dissolution, uses the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, after saturated nacl aqueous solution is washed, after organic over anhydrous dried over sodium sulfate, remove solvent under reduced pressure, column chromatography obtains white solid 1.5g, productive rate 85%.
b)
The white solid (1.64mmol) of gained in 580mg18a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 337mg Boc-Ser-OH (1.64mmol) respectively, 624mgHATU (1.64mmol), 531mgDIEA (4.1mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, and after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, evaporated under reduced pressure, and column chromatography obtains white solid 542mg, productive rate 75%.
c)
The white solid (0.45mmol) of gained in 200mg18b is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 103mg3-phenoxy group toluylic acid (0.45mmol) respectively, 171mgHATU (0.45mmol), 145mgDIEA (1.13mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after acetic acid ethyl dissolution, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, after organic over anhydrous dried over sodium sulfate, evaporated under reduced pressure, column chromatography obtains white solid 130mg, productive rate 52.6%.mp:145.0-146.0℃;
1H-NMR(DMSO-d
6):δ9.54(s,1H),8.25-8.18(m,2H),7.24(d,1H,J=9.0Hz),7.36(t,2H,J=7.5Hz),7.27(t,1H,J=7.5Hz),7.11(t,1H,J=7.5Hz),7.03-6.94(m,5H),6.83(d,1H,J=9.0Hz),6.35-6.28(m,2H),4.99(t,1H,J=4.5Hz),4.41-4.35(m,1H),4.19-4.08(m,3H),3.64(s,3H),3.55-3.50(m,2H),3.48(s,2H),2.0-1.93(m,1H),0.78-0.74(m,6H);MS-ESIm/z:550[M+H]
+。
Embodiment 19:WK-4-46
The white solid (0.31mmol) of gained in 135mg18b is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 103mg3-indolylacetic acid (0.31mmol) respectively, 118mgHATU (0.31mmol), 101mgDIEA (0.78mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after acetic acid ethyl dissolution, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, after organic over anhydrous dried over sodium sulfate, evaporated under reduced pressure, column chromatography obtains white solid 90mg, productive rate 59%.mp:198.0-200.0℃;
1H-NMR(CD
3OD)δ7.56(d,1H,J=9.0Hz),7.34(d,1H,J=9.0Hz),7.20(s,1H),7.12-7.00(m,3H),6.35-6.31(m,2H),4.52-4.45(m,1H),4.24-4.15(m,3H),3.81-3.75(m,1H),3.73(s,2H),3.67(s,3H),3,69(m,1H),2.04-1.98(m,1H),0.84-0.77(m,6H);MS-ESI m/z:497[M+H]
+。
Embodiment 20:WK-4-43
a)
The white solid (1.19mmol) of gained in 420mg18a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 260mg Boc-Thr-OH (1.19mmol) respectively, 452mgHATU (1.19mmol), 388mgDIEA (3mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, evaporated under reduced pressure, column chromatography obtains white solid 505mg, productive rate 93.6%.
b)
The white solid (0.6mmol) of gained in 272mg20a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 137mg3-phenoxy group toluylic acid (0.6mmol) respectively, 228mgHATU (0.6mmol), 194mgDIEA (1.5mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after acetic acid ethyl dissolution, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, after organic over anhydrous dried over sodium sulfate, evaporated under reduced pressure, column chromatography obtains white solid 65mg, productive rate 20%.mp:135.0-136.0℃;
1H-NMR(DMSO-d
6):δ9.56(s,1H),8.31-8.27(m,1H),8.06(d,1H,J=8.4Hz),7.66(d,1H,J=8.4Hz),7.38(t,2H,J=8.0Hz),7.29(t,1H,J=8.0Hz),7.13(t,1H,J=7.4Hz),7.06(d,1H,J=7.8Hz),7.01-6.97(m,4H),6.85(d,1H,J=7.8Hz),6.37-6.30(m,2H),4.95(d,1H,J=4.8Hz),4.41-4.35(m,1H),4.32-4.28(m,1H),4.2-4.1(m,3H),3.98-3.92(m,1H),3.66(s,3H),3.56-3.52(m,2H),2.00-1.91(m,1H),0.95(d,3H,J=6.0Hz),0.82-0.78(m,6H);MS-ESI m/z:564[M+H]
+。
Embodiment 21:WK-4-48
The white solid (0.33mmol) of gained in 150mg20a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 58mg3-indolylacetic acid (0.33mmol) respectively, 126mgHATU (0.33mmol), 107mgDIEA (0.83mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after acetic acid ethyl dissolution, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, after organic over anhydrous dried over sodium sulfate, evaporated under reduced pressure, column chromatography obtains white solid 83mg, productive rate 49%.mp:94.0-95.0℃;
1H-NMR(DMSO-d
6):δ10.84(s,1H),9.54(s,1H),8.29-8.25(m,1H),7.77(d,1H,J=6.0Hz),7.64(d,1H,J=9.0Hz),7.53(d,1H,J=9.0Hz),7.31(d,1H,J=6.0Hz),7.20(s,1H),7.06-6.91(m,2H),6.34-6.29(m,2H),4.92(d,1H,J=3.0Hz),4.32-4.28(m,1H),4.20-4.08(m,3H),3.97-3.92(m,1H),3.64-3.60(m,4H),1.97-1.91(m,1H),0.95(d,3H,J=6.0Hz),0.80-0.76(m,6H);MS-ESI m/z:511[M+H]
+。
Embodiment 22:WK-5-5
a)
The white solid (1.31mmol) of gained in 463mg18a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 285mg Boc-Val-OH (1.31mmol) respectively, 498mgHATU (1.31mmol), 423mgDIEA (3.27mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, evaporated under reduced pressure, column chromatography obtains white solid 427mg, productive rate 72.4%.
b)
The white solid (0.44mmol) of gained in 200mg22a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 100mg3-phenoxy group toluylic acid (0.44mmol) respectively, 167mgHATU (0.44mmol), 142mgDIEA (1.1mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after acetic acid ethyl dissolution, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, after organic over anhydrous dried over sodium sulfate, evaporated under reduced pressure, column chromatography obtains white solid 55mg, productive rate 22%.mp:140.0-141.0℃;
1H-NMR(CD
3OD):δ7.35-7.24(m,3H),7.10-7.02(m,3H),6.99-6.94(m,3H),6.85(d,1H,J=9.0Hz),6.35-6.31(m,2H),4.24(d,2H,J=6.0Hz),4.19-4.08(m,2H),3.71(s,3H),3.52(d,2H,J=6.0Hz),2.05-1.96(m,2H),0.87-0.84(m,12H);MS-ESI m/z:562[M+H]
+。
Embodiment 23:WK-5-7
The white solid (0.44mmol) of gained in 200mg22a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 77mg3-indolylacetic acid (0.44mmol) respectively, 167mgHATU (0.44mmol), 142mgDIEA (1.1mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after acetic acid ethyl dissolution, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, after organic over anhydrous dried over sodium sulfate, evaporated under reduced pressure, column chromatography obtains white solid 65mg, productive rate 29%.mp:145-146℃;
1H-NMR(DMSO-d
6):δ10.81(s,1H),9.54(s,1H),8.23-8.19(m,1H),7.83(d,2H,J=9.0Hz),7.52(d,1H,J=6.0Hz),7.30(d,1H,J=9.0Hz),7.16(s,1H),7.05-6.89(m,3H),6.33(d,1H,J=3.0Hz),6.28(dd,1H,J=9.0,3.0Hz),4.23-4.18(m,1H),4.14-4.09(m,3H),3.64(s,3H),3.55-3.50(m,2H),1.97-1.86(m,2H),0.78-0.74(m,12H);MS-ESI m/z:509[M+H]
+。
Embodiment 24:WK-3-26
a)
The white solid (1.13mmol) of gained in 400mg18a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 278mg Boc-Gln-OH (1.13mmol) respectively, 430mgHATU (1.13mmol), 365mgDIEA (2.83mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, evaporated under reduced pressure, ethyl acetate is washed, and filters to obtain white solid 420mg, productive rate 77%.
b)
The white solid (0.46mmol) of gained in 220mg24a is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 175mg3-phenoxy group toluylic acid (0.46mmol) respectively, 175mgHATU (0.46mmol), 149mgDIEA (1.15mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after acetic acid ethyl dissolution, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, evaporated under reduced pressure, washes by ethyl acetate, filters to obtain white solid 205mg, productive rate 75.6%.mp:195.0-196.0℃;
1H-NMR(DMSO-d
6)δ8.29(d,2H,J=6Hz),7.78(d,1H,J=6Hz),7.36-7.24(m,4H),7.11(t,1H,J=7.5Hz),7.02-6.93(m,5H),6.83-6.75(m,2H),6.34-6.27(m,2H),4.30-4.24(m,1H),4.15-4.10(m,3H),3.63(s,3H),3.44(s,2H),2.07-2.02(m,2H),1.91-1.84(m,2H),1.74-1.66(m,1H),0.75-0.72(m,6H);MS-ESI m/z:591[M+H]
+。
Embodiment 25:WK-2-36
a)
6.04g Boc-L-Asn (26mmol) is dissolved in 150mLDMF, adds 9.8g Valine benzyl ester tosilate (26mmol) respectively, 9.89gHATU (26mmol), 8.4gDIEA (65mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after acetic acid ethyl dissolution, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, after remaining organic over anhydrous dried over sodium sulfate, remove solvent under reduced pressure, obtain white solid 10g, productive rate 91%.
b)
The white solid (5mmol) of gained in 2.11g25a is dissolved in 50mL anhydrous methanol, adds 211mg10%Pd/C, H
2lower stirring reaction overnight, within second day, TLC detects, and react completely, filtered off through Celite Pd/C, removes solvent under reduced pressure, obtains white solid 1.6g, productive rate 96%.
c)
The white solid (3mmol) of gained in 994mg25b is dissolved in 30mLDMF, adds 737mgL-allothreonine benzyl ester (3mmol) respectively, 1.141gHATU (3mmol), 970mgDIEA (7.5mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after acetic acid ethyl dissolution, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution is washed, after remaining organic over anhydrous dried over sodium sulfate, remove solvent under reduced pressure, obtain white solid 1.33g, productive rate 85%.
d)
In 300mg25c, the white solid (0.57mmol) of gained is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 71mg pyrazine carboxylic acid (0.57mmol) respectively, 217mgHATU (0.57mmol), 184mgDIEA (1.43mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filters to obtain white solid 155mg, productive rate 51.5%.mp:205℃-206℃.
1H-NMR(CD
3OD,300MHz)δ9.23(s,1H),8.79(s,1H),8.69(s,1H),7.36-7.31(m,5H),5.16(s,2H),5.00-4.96(m,1H),4.44(d,1H,J=6.0Hz),4.27(d,1H,J=6.0Hz),4.08(t,1H,J=6.0Hz),2.83(t,2H,J=6.0Hz),2.11-2.05(m,1H),1.21(d,3H,J=6.0Hz),0.89(d,6H,J=6.0Hz);MS-ESIm/z:529[M+H]
+。
Embodiment 26:WK-2-29
In 350mg25c, the white solid (0.66mmol) of gained is dissolved in 8mL methylene dichloride, and add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, TLC detects, react completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 158mg3 respectively, 4,5-trimethoxy phenylpropionic acid (0.66mmol), 251mgHATU (0.66mmol), 213mgDIEA (1.65mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filters to obtain white solid 220g, productive rate 51.7%.mp:241℃-242℃.
1H-NMR(DMSO-d6,300MHz)δ8.35(d,1H,J=6.0Hz),8.27(d,1H,J=9.0Hz),7.62(d,1H,J=9.0Hz),7.42(s,1H),6.89(s,5H),6.88(s,1H),6.51(s,2H),5.14(d,1H,J=6Hz),5.10(s,2H),4.64-4.60(m,1H),4.28-4.22(m,2H),3.98-3.92(m,1H),3.74(s,6H),3.61(s,6H),2.76-2.71(m,2H),2.45-2.36(m,4H),1.98-1.92(m,2H),1.11(d,3H,J=6.0Hz),0.79(d,3H,J=6.0Hz),0.74(d,3H,J=6.0Hz).MS-ESI m/z:645[M+H]
+。
Embodiment 27:WK-2-46
In 214mg25c, the white solid (0.41mmol) of gained is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 84mg4-cyclohexylbenzoic acid (0.41mmol) respectively, 156mgHATU (0.41mmol), 156mgDIEA (0.41mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, washes by ethyl acetate, filters to obtain white solid 105mg, productive rate 43%.mp:219℃-220℃.
1H-NMR(CD
3OD,300MHz)δ7.82-7.77(m,2H),7.37-7.33(m,7H),5.19(s,2H),4.97-4.94(m,1H),4.48-4.46(m,1H),4.32-4.30(m,1H),4.13-4.11(m,1H),2.83-2.77(m,2H),2.60-2.54(m,1H),2.09-2.07(m,1H),1.85-1.75(m,5H),1.47-1.42(m,4H),1.23-1.20(m,4H),0.90-0.88(m,4H).MS-ESI m/z:609[M+H]
+。
Embodiment 28:WK-4-22
In 300mg25c, the white solid (0.57mmol) of gained is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 100mg3-indolylacetic acid (0.57mmol) respectively, 217mgHATU (0.57mmol), 184mgDIEA (0.57mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, remove solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, after evaporated under reduced pressure, washes by ethyl acetate, filter to obtain pale red solid 146mg, productive rate 44%.mp:234℃-235℃.
1H-NMR(DMSO-d6,300MHz)δ10.85(brs,1H),8.26(d,2H,J=6.0Hz),7.58-7.51(m,2H),7.35-7.31(m,6H),7.19(s,1H),7.05(t,1H,J=6.0Hz),6.97-6.89(m,2H),5.10(s,2H),5.06(d,1H,J=6.0Hz),4.65-4.58(m,1H),4.25(t,1H,J=6.0Hz),3.96-3.90(m,1H),3.55(s,2H),2.58-2.50(m,1H),2.42-2.34(m,1H),1.92-1.82(m,1H),1.10(d,3H,J=6.0Hz),0.72(d,3H,J=6.0Hz),0.65(d,3H,J=6.0Hz);MS-ESI m/z:580[M+H]
+。
Embodiment 29:WK-4-24
In 300mg25c, the white solid (0.57mmol) of gained is dissolved in 8mL methylene dichloride, add 2mL trifluoroacetic acid, stirring at room temperature is after 2 hours, and TLC detects, and reacts completely, remove solvent under reduced pressure, obtain white solid, be dissolved in 20mLDMF, add 121mg4-felbinac (0.57mmol) respectively, 217mgHATU (0.57mmol), 184mgDIEA (0.57mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, remove solvent under reduced pressure, after dissolving with ethyl acetate portion, use the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution, distillation washing, evaporated under reduced pressure, wash by ethyl acetate, recrystallizing methanol after filtering, obtains white solid 107mg, productive rate 30%.mp:242℃-243℃.
1H-NMR(DMSO-d
6,300MHz)δ8.44(d,1H,J=6.0Hz),8.20(d,1H,J=6.0Hz),7.64-7.54(m,6H),7.47-7.42(m,3H),7.35-7.33(m,5H),6.90(s,1H),5.01(d,1H,J=6.0Hz),4.63-4.60(m,1H),4.26-4.14(m,2H,J=6.0Hz),3.90-3.85(m,1H),3.58(s,3H),3.50(s,2H),2.62-2.53(m,1H),2.42-2.34(m,1H),1.93-1.88(m,1H),1.09(d,3H,J=6.0Hz),0.76(d,3H,J=6.0Hz),0.69(d,3H,J=6.0Hz);MS-ESI m/z:617[M+H]
+。
Embodiment 30:WK-5-3
The white solid (0.45mmol) of gained in 200mg13b is dissolved in 20mLDMF, add 77mgL-threonine methyl ester hydrochloric salt (0.45mmol) respectively, 172mgHATU (0.45mmol), 162mgDIEA (1.13mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving, uses the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution with ethyl acetate portion, and distillation washing, filters to obtain white solid 180mg, productive rate 71.4%.mp:215-217℃.
1H-NMR(DMSO-d
6,300MHz)δ:8.38(d,1H,J=6.0Hz),8.00(d,1H,J=6.0Hz),7.59(d,1H,J=9.0Hz),7.39-7.34(m,3H),7.26(t,1H,J=7.5Hz),7.11(t,1H,J=6.0Hz),7.02-6.96(m,2H),6.92-6.88(m,2H),6.83-6.81(m,2H),4.95-4.93(m,1H),4.62-4.55(m,2H),4.25-4.20(m,2H),4.12-4.04(m,1H),3.59(s,3H),3.43(s,2H),2.60-2.52(m,1H),2.38-2.30(m,1H),1.99-1.94(m,1H),1.04(d,1H,J=6.0Hz),0.77(d,3H,J=6.6Hz),0.70(d,3H,J=8.1Hz);MS-ESI m/z:557[M+H]
+。
Embodiment 31:WK-5-1
The white solid (0.45mmol) of gained in 200mg13b is dissolved in 20mLDMF, add 70mgL-serine methyl ester hydrochloride (0.45mmol) respectively, 172mgHATU (0.45mmol), 146mgDIEA (1.133mmol).Stirred overnight at room temperature, TLC detects, and reacts completely, removes solvent under reduced pressure, after dissolving, uses the hydrochloric acid soln of 1mol/L respectively, saturated sodium carbonate solution, saturated nacl aqueous solution with ethyl acetate portion, and distillation washing, filters to obtain white solid 143mg, productive rate 58%.mp:165.0-166.0℃.
1H-NMR(DMSO-d6,300MHz)δ8.41(d,1H,J=8.1Hz),8.28(d,1H,J=7.2Hz),7.55(d,1H,J=9.0Hz),7.41-7.36(m,3H),7.28(t,1H,J=7.8Hz),7.13(t,1H,J=7.2Hz),7.04-6.98(m,2H),6.94-6.90(m,2H),6.85-6.82(m,2H),4.62-4.56(m,1H),4.30-4.23(m,2H),3.69-3.63(m,2H),3.61(s,3H),3.45(s,2H),2.60-2.53(m,1H),2.39-2.32(m,1H),1.98-1.92(m,1H),0.73(d,3H,J=6.6Hz),0.71(d,3H,J=8.1Hz);MS-ESI m/z:543[M+H]
+。
Embodiment 32:XK-5-35
The white solid (0.5mmol) of gained in 220mg13b is dissolved in 20mLDMF, add L-allo-Thr-OBzl105mg (0.5mmol) respectively, 190mgHATU (0.5mmol), 161mgDIEA (1.25mmol).Stirred overnight at room temperature, removes solvent under reduced pressure, column chromatography, obtains product 268mg, productive rate 84.7%.mp:180.0-183.0℃；
1H-NMR(CD
3OD)δ:7.29-7.17(m,8H),7.05-6.96(m,2H),6.92-6.89(m,3H),6.77(d,1H,J=8.7Hz),5.14-5.05(m,2H),4.66(t,1H,J=6.6Hz),4.36(d,1H,J=6.0Hz),4.16(d,1H,J=6.0Hz),3.47(s,2H),2.70-2.63(m,1H),2.56-2.49(m,1H),2.04-1.98(m,1H),1.17-1.13(m,3H),0.78-0.72(m,6H);MS-ESIm/z:633[M+H]
+。
Embodiment 33:XK-7-30
The white solid (0.5mmol) of gained in 220mg13b is dissolved in 20mLDMF, add L-allothreonine methyl esters 67mg (0.5mmol) respectively, 190mgHATU (0.5mmol), 161mgDIEA (1.25mmol).Stirred overnight at room temperature, removes solvent under reduced pressure, column chromatography, obtains product 204mg, productive rate 64.6%.mp:180.0-183.0℃;
1H-NMR(CD
3OD)δ:7.27(t,2H,J=6.0Hz),7.21(t,1H,J=6.0Hz),7.05-6.98(m,2H),6.92-6.90(m,3H),6.78(d,1H,J=6.0Hz),4.68(t,1H,J=5.1Hz),4.31(d,1H,J=4.2Hz),4.17(d,1H,J=4.8Hz),4.01-3.95(m,1H),3.64(s,3H),3.47(s,2H),2.79(q,1H,J=5.1,11.7Hz),2.55(q,1H,J=7.2,11.7Hz),2.08-1.99(m,1H),1.16(d,3H,J=4.8Hz),0.83-0.78(m,6H);MS-ESI m/z:633[M+H]
+。
Embodiment 34:XK-6-16
The white solid (1mmol) of gained in 632mg32a is dissolved in 20mL methyl alcohol, adds 10%Pd/C, stirring under hydrogen.Stirred overnight at room temperature, filters, removes solvent under reduced pressure, obtain product 630mg, productive rate 99%.mp:215-218℃;
1H-NMR(CD
3OD)δ:7.27(t,2H,J=5.7Hz),7.20(t,1H,J=6.0Hz),7.04-6.98(m,2H),6.92-6.90(m,3H),6.77(d,1H,J=6.0Hz),4.68(t,1H,J=4.8Hz),4.32(d,1H,J=4.5Hz),4.05-3.99(m,1H),3.47(s,2H),2.68(q,1H,J=5.1,11.7Hz),2.55(q,1H,J=5.1，11.7Hz),2.09-2.00(m,1H),1.17(d,3H,J=4.8Hz),0.84-0.79(m,6H);MS-ESI m/z:543[M+H]
+。
Pharmacological experimental example: compound of the present invention is to the restraining effect of mankind 20S proteasome
Method:
The 20S proteasome test kit purchased from Calbiochem (San Diego, CA, USA) is adopted to measure.By using Bio Tek photofluorometer (Winooski under proteasome agonist PA28 (16 μ g/mL) existent condition, Vermont, USA) measure fluorogenic substrate Suc-Leu-Leu-Val-Try-AMC under different proteasome inhibitor concentration and be hydrolyzed the fluorescence that produces to determine the restraining effect of proteasome inhibitor to the chymase avtive spot of mankind 20S proteasome.Specific experiment method refers to document Dang, Lin, Ho, Soroka, Lee, Huang, Chen.Bioorg.Med.Chem.Lett.2011, and 21,1926.
Result:
The chymase avtive spot (CT-L) of compound of the present invention to mankind 20S proteasome has obvious restraining effect.Part of compounds is to the half effective inhibition concentration (IC of the chymase avtive spot (CT-L) of 20S proteasome
50) as shown in table 1.
Table 1. test-compound is to the restraining effect of the CT-L avtive spot of mankind 20S proteasome
*iC
50value is the mean number of twice independently active Inhibition test result of proteasome chymase of enzyme level.
Claims (28)
1. the dipeptide compound represented by following general formula (I) and steric isomer thereof and physiologically acceptable salt
Wherein, L is selected from covalent linkage ,-CO-, or-(CH
2) n-, n=1,2;
R
1be selected from substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl;
R
2be selected from substituted or unsubstituted C1-C6 straight or branched alkyl;
R
3be selected from (CH
2) mCONH
2, m=1,2,3, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
4be selected from substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substituted or unsubstituted indyl, substituted or unsubstituted quinolyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted cumarone ketone group;
Substituting group is selected from hydroxyl, amino, halogen, phenyl, C1-C3 alkyl, C1-C3 haloalkyl, aryloxy, C1-C3 alkoxyl group, sweet-smelling formacyl, benzyloxy.
2. compound according to claim 1, is characterized in that, described compound is the compound shown in general formula (IA) and steric isomer thereof and physiologically acceptable salt:
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
4be selected from substituted or unsubstituted phenyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substituted or unsubstituted indyl, substituted or unsubstituted quinolyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzofuranone;
Substituting group is selected from hydroxyl, amino, halogen, phenyl, C1-C3 alkyl, C1-C3 haloalkyl, aryloxy, C1-C3 alkoxyl group, sweet-smelling formacyl, benzyloxy.
3. compound according to claim 2, is characterized in that, described compound is the compound shown in general formula (IAa) and steric isomer thereof and physiologically acceptable salt:
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
41, R
42separately be selected from hydrogen, methoxyl group, trifluoromethyl, substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy group, substituted or unsubstituted benzoyl;
Substituting group is selected from hydroxyl, amino, halogen, phenyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
4. compound according to claim 2, is characterized in that, described compound is the compound shown in general formula (IAb) and steric isomer thereof and physiologically acceptable salt:
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group;
R
43be selected from hydrogen, halogen, hydroxyl, amino, nitro.
5. compound according to claim 2, is characterized in that, described compound is the compound shown in general formula (IAc) and steric isomer thereof and physiologically acceptable salt:
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group;
R
44be selected from hydrogen, halogen, hydroxyl, amino, nitro.
6. compound according to claim 2, is characterized in that, described compound is the compound shown in general formula (IAd) and steric isomer thereof and physiologically acceptable salt:
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
45, R
46separately be selected from substituted or unsubstituted C1-C6 straight or branched alkyl;
Substituting group is selected from hydroxyl, amino, halogen, phenyl, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
7. compound according to claim 2, is characterized in that, described compound is the compound shown in general formula (IAe) and steric isomer thereof and physiologically acceptable salt:
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
47be selected from hydrogen, halogen, hydroxyl, amino, nitro;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
8. compound according to claim 2, is characterized in that, described compound is the compound shown in general formula (IAf) and steric isomer thereof and physiologically acceptable salt:
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group;
R
48be selected from hydrogen, halogen, hydroxyl, amino, nitro.
9. compound according to claim 1, is characterized in that, described compound is the compound shown in general formula (IB) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
49be selected from substituted or unsubstituted benzyloxy;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
10. compound according to claim 1, is characterized in that, described compound is the compound shown in general formula (IC) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
410be selected from hydrogen, halogen, hydroxyl, amino, nitro;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
11. compounds according to claim 1, is characterized in that, described compound is the compound shown in general formula (ID) and steric isomer thereof and physiologically acceptable salt
R
13be selected from hydrogen, halogen, hydroxyl, amino, nitro;
R
411be selected from substituted or unsubstituted phenoxy group;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
12. compounds according to claim 1, is characterized in that, described compound is the compound shown in general formula (IE) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
412be selected from substituted or unsubstituted phenoxy group.
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
13. compounds according to claim 1, is characterized in that, described compound is the compound shown in general formula (IF) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
31, R
32separately be selected from hydrogen, hydroxyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
413be selected from substituted or unsubstituted phenoxy group;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
14. compounds according to claim 1, is characterized in that, described compound is the compound shown in general formula (IG) and steric isomer thereof and physiologically acceptable salt
R
11, R
12separately be selected from hydrogen, halogen, hydroxyl, amino, nitro, substituted or unsubstituted C1-C6 straight or branched alkoxyl group, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
31, R
32separately be selected from hydrogen, hydroxyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group;
R
414be selected from hydrogen, halogen, hydroxyl, amino, nitro.
15. 1 kinds of tripeptide compounds and steric isomer thereof and physiologically acceptable salt represented by following general formula (II):
Wherein, M is selected from-(CH
2)
n-, n=0,1,2;
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
6be selected from hydrogen, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
7be selected from substituted or unsubstituted C1-C6 straight or branched alkyl;
R
8be selected from (CH
2) mCONH
2, m=1,2,3, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
9be selected from substituted or unsubstituted phenyl, substituted or unsubstituted phenoxy group, substituted or unsubstituted pyrazinyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted furyl, substituted or unsubstituted indyl;
Substituting group is selected from hydroxyl, amino, halogen, phenyl, C1-C3 alkyl, C1-C3 haloalkyl, aryloxy, C1-C3 alkoxyl group, sweet-smelling formacyl, benzyloxy.
16. compounds according to claim 15, is characterized in that, described compound is the compound shown in general formula (IIA) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
91, R
92separately be selected from hydrogen, substituted or unsubstituted phenoxy group, substituted or unsubstituted phenyl;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
17. compounds according to claim 15, is characterized in that, described compound is the compound shown in general formula (IIB) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
93be selected from substituted or unsubstituted phenoxy group, substituted or unsubstituted phenyl;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
18. compounds according to claim 15, is characterized in that, described compound is the compound shown in general formula (IIC) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group;
R
94be selected from hydrogen, halogen, hydroxyl, amino, nitro.
19. compounds according to claim 15, is characterized in that, described compound is the compound shown in general formula (IID) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group;
R
95be selected from C3-C6 cycloalkyl.
20. compounds according to claim 15, is characterized in that, described compound is the compound shown in general formula (IIE) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group;
R
96be selected from hydrogen, halogen, hydroxyl, amino, nitro.
21. compounds according to claim 15, is characterized in that, described compound is the compound shown in general formula (IIF) and steric isomer thereof and physiologically acceptable salt
R
5be selected from hydrogen, substituted or unsubstituted benzyl, substituted or unsubstituted C1-C6 straight or branched alkyl;
R
97, R
98, R
99separately be selected from substituted or unsubstituted C1-C6 straight or branched alkoxyl group;
Substituting group is selected from hydroxyl, amino, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxyl group.
22. compounds any one of claim 1-21, it is characterized in that, described compound is selected from:
Any one of 23. claim 1-14, the preparation method of compound, is characterized in that, comprises the following steps:
The formula V compound that formula III compound and formula IV compound generate through condensation reaction, formula V compound is through deprotection reaction production VI compound, formula VI compound and formula VII compound are through condensation reaction production VIII compound, formula VIII compound is through deprotection reaction production IX compound, and formula IX compound and formula X compound are through condensation reaction production I;
Wherein, L, R
1, R
2, R
3and R
4definition the same.
Any one of 24. claim 15-21, the preparation method of compound, is characterized in that, comprises the following steps:
The formula XIII compound that formula XI compound and formula XII compound generate through condensation reaction, formula XIII compound is through deprotection reaction production XIV compound, formula XIV compound and formula XV compound are through condensation reaction production XVI compound, formula XVI compound is through deprotection reaction production XVII compound, and formula XVII compound and formula XVIII compound are through condensation reaction production II compound;
Wherein, M, R
5, R
6, R
7, R
8and R
9definition the same.
The composition of 25. 1 kinds of arbitrary compounds according to any one of claim 1-22 containing effective dose and pharmaceutically acceptable carrier medicine.
26. compounds according to any one of claim 1-22 are as the purposes of proteasome inhibitor.
27. compounds according to any one of claim 1-22 are for the preparation of the application in the medicine of prevention or treatment and proteasome relative disease.
28. application according to claim 28, described disease is selected from the diseases such as tumour, autoimmune disorder, inflammation.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN107417767A (en) * | 2016-08-18 | 2017-12-01 | 杭州市西溪医院 | Dipeptide compound, its preparation method and the application of piperidines or piperazine structure |
| CN108164583A (en) * | 2018-01-12 | 2018-06-15 | 珠海诺贝尔国际生物医药研究院有限公司 | Proteasome inhibitor and its application |
| CN112920075A (en) * | 2021-02-01 | 2021-06-08 | 深圳海创生物科技有限公司 | Amide compound, composition and application of amide compound and composition in preparation of products with antioxidant or anti-inflammatory effects |
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| WO2008033807A2 (en) * | 2006-09-13 | 2008-03-20 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Synergistic combinations of antineoplastic thiol-binding mitochondrial oxidants and antineoplastic proteasome inhibitors for the treatment of cancer |
| CN101928329A (en) * | 2009-06-19 | 2010-12-29 | 北京大学 | Tripeptide boric acid (ester) compound and preparation method and application thereof |
| CN102428075A (en) * | 2009-03-20 | 2012-04-25 | 欧尼斯治疗公司 | Crystalline tripeptide epoxy ketone protease inhibitors |
-
2014
- 2014-04-03 CN CN201410133493.6A patent/CN104974221B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008033807A2 (en) * | 2006-09-13 | 2008-03-20 | The Arizona Board Of Regents On Behalf Of The University Of Arizona | Synergistic combinations of antineoplastic thiol-binding mitochondrial oxidants and antineoplastic proteasome inhibitors for the treatment of cancer |
| CN102428075A (en) * | 2009-03-20 | 2012-04-25 | 欧尼斯治疗公司 | Crystalline tripeptide epoxy ketone protease inhibitors |
| CN101928329A (en) * | 2009-06-19 | 2010-12-29 | 北京大学 | Tripeptide boric acid (ester) compound and preparation method and application thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107417767A (en) * | 2016-08-18 | 2017-12-01 | 杭州市西溪医院 | Dipeptide compound, its preparation method and the application of piperidines or piperazine structure |
| CN107417767B (en) * | 2016-08-18 | 2021-09-03 | 杭州市西溪医院 | Dipeptide compound constructed by piperidine or piperazine, preparation method and application thereof |
| CN108164583A (en) * | 2018-01-12 | 2018-06-15 | 珠海诺贝尔国际生物医药研究院有限公司 | Proteasome inhibitor and its application |
| CN112920075A (en) * | 2021-02-01 | 2021-06-08 | 深圳海创生物科技有限公司 | Amide compound, composition and application of amide compound and composition in preparation of products with antioxidant or anti-inflammatory effects |
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